Systems and methods for increasing reaction yield

ABSTRACT

The invention generally relates to systems and methods for increasing reaction yield. In certain embodiments, the invention provides systems for increasing a yield of a chemical reaction that include a pneumatic sprayer configured to generate a liquid spray discharge from a solvent. The solvent includes a plurality of molecules, a portion of which react with each other within the liquid spray discharge to form a reaction product. The system also includes a collector positioned to receive the liquid spray discharge including the unreacted molecules and the reaction product. The system also includes a recirculation loop connected from the collector to the pneumatic sprayer in order to allow the unreacted molecules and the reaction product to be recycled through the pneumatic sprayer, thereby allowing a plurality of the unreacted molecules to react with each other as the unreacted molecules cycle again through the system.

RELATED APPLICATION

This application claims the benefit of and priority to U.S. provisionalapplication Ser. No. 62/374,144, filed Aug. 12, 2016, the content ofwhich is incorporated by reference herein in its entirety.

GOVERNMENT INTEREST

This invention was made with government support under W911NF-16-2-0020awarded by the Defense Advanced Research Projects Agency (DARPA). Thegovernment has certain rights in the invention.

FIELD OF THE INVENTION

The invention generally relates to systems and methods for increasingreaction yield.

BACKGROUND

Acceleration of the rates of ordinary organic reactions in droplets bylarge factors has been reported. The acceleration is partly the resultof solvent evaporation and the resulting increase in reagentconcentrations. However, there is also evidence of intrinsic reactionacceleration at the surfaces of droplets, so that the increased surfaceto volume ratio of microdroplets plays a significant role in reactionacceleration. In several studies, the distance of travel of droplets ina spray correlates roughly with the extent of reaction, suggesting thatevaporation which creates smaller droplets also increases reactionrates.

However, there is a limit as to how far the droplets can travel withinthe spray. Accordingly, a problem with using spray techniques togenerate reaction products is that reactions do not go to completion andproduct yield can be low.

SUMMARY

The invention provides systems and methods for increasing reaction yieldfor reactions conducted in a liquid spray discharge. Aspects of theinvention are accomplished by using a system with a recirculationfunction. In that manner, if a reaction is incomplete, the sprayedmaterial can be collected and resprayed in order to be processed one ormore times. That provides unreacted molecules a chance to react andallows incomplete reactions to be driven to completion, therebyincreasing a yield of a chemical reaction. In a preferred approach, thesolvent may be condensed and reused so that the collected materialincluding unreacted reagents and reaction products is taken up again inthe body of the solution being resprayed. In that way, a continuousprocess maximizes product yields and saves solvent.

In certain aspects, the invention provides systems for increasing ayield of a chemical reaction that include a pneumatic sprayer configuredto generate a liquid spray discharge from a solvent. The solventincludes a plurality of molecules, a portion of which react with eachother within the liquid spray discharge to form a reaction product. Thesystem also includes a collector positioned to receive the liquid spraydischarge including the unreacted molecules and the reaction product.The system also includes a recirculation loop connected from thecollector to the pneumatic sprayer in order to allow the unreactedmolecules and the reaction product to be recycled through the pneumaticsprayer, thereby allowing a plurality of the unreacted molecules toreact with each other as the unreacted molecules cycle again through thesystem.

The system may further include a voltage source operably associated withthe pneumatic sprayer in order to generate a charged liquid spraydischarge. The collector may include one or more of the followingcomponents. In certain embodiments, the collector includes anelectrostatic precipitator. The collector may also include a liquiddegassing unit within a vacuum chamber positioned after theelectrostatic precipitator, thereby allowing gas from the pneumaticsprayer to be released from the system. An exemplary liquid degassingunit is one that includes a semi-permeable membrane within the vacuumchamber. The collector may also include a condenser positioned after theliquid degassing outlet within the vacuum chamber. An exemplarycondenser is a cryogenic condenser. The system may also include a massspectrometer (either on-line or offline). In certain embodiments, thepneumatic sprayer is an electrosonic spray ionization source. The systemmay also include an elongate member between the pneumatic sprayer andthe collector.

Other aspects of the invention provide methods for increasing yield of achemical reaction that involve generating a liquid spray discharge usinga pneumatic sprayer. The liquid spray discharge is generated from asolvent that includes a plurality of molecules, a portion of which reactwith each other within the liquid spray discharge to form a reactionproduct. The method then involves collecting in a collector the liquidspray discharge including unreacted molecules and the reaction product.The method then involves recirculating the unreacted molecules and thereaction product through the pneumatic sprayer in order to allow aplurality of the unreacted molecules in the solvent to react with eachother as the unreacted molecules cycle again through the pneumaticsprayer, thereby increasing a yield of the chemical reaction.

In certain embodiments, a voltage source is operably associated with thepneumatic sprayer in order to generate a charged liquid spray discharge.Collecting may involve condensing the liquid spray discharge into areservoir of the collector, using for example, a cryogenic condenser.Collecting may further involve precipitating liquid droplets prior tothe condensing step. Collecting may also involve degassing gas used bythe pneumatic sprayer to generate the liquid spray discharge. In certainembodiments, degassing uses a liquid degassing unit including asemi-permeable membrane within a vacuum chamber. The method mayadditionally involve analyzing the reaction product, which may bethrough use of a bench-top mass spectrometer or miniature massspectrometer. In certain embodiments, the pneumatic sprayer is anelectrosonic spray ionization source. The methods of the invention mayfurther involve controlling an extent of formation of the reactionproduct by varying a distance between the pneumatic sprayer and thecollector.

In other aspects, the invention provides systems that include an inletport, a droplet forming region, and a condensing region. The dropletforming region and the liquid condensing region are operably coupled toeach other to via tubing to form a circulating loop for flow such that aportion of reagents introduced via the inlet port react with each otherin droplets formed in the droplet forming region to produce reactionproduct. The reaction product is condensed along with unreacted reagentsin the condensing region. The reaction product and the unreactedreagents are re-circulated through the system one or more times, therebyallowing the unreacted reagents to react with each other as theunreacted reagents cycle again through the system.

In certain embodiments, the droplet forming region includes a flowregulating valve (such as a needle valve) and an evaporator. In certainembodiments, the condensing region includes a condenser. The system mayfurther include a pump. The pump may be a compressor, which is situatedbetween the evaporator and the condenser.

In certain embodiments, a portion of the tubing is transparent, allowingfor observation of flow within the system. In other or additionalembodiments, the system includes or more pressure sensors. In other oradditional embodiments, the system also includes an outlet port. Theoutlet port may be coupled to an outlet tube that is operably associatedwith a voltage source in a manner that an electrospray plum is generatedat a distal end of the outlet tube. In such embodiments, the system mayfurther include an analytical instrument, such as a mass spectrometer,operably associated with the system to receive the spray generated atthe distal end of the outlet tube. In other embodiments, the outletallows for extraction of reaction product from the system for off-lineanalysis.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic showing an embodiment of the invention inn whichthe collector includes a condenser.

FIG. 2 is a schematic example of solvent condensation using a condenser.

FIG. 3 is a photograph and schematic showing a six silver wireelectrostatic precipitator that precipitates small positively chargedmicrodroplets from the liquid spray discharge of the pneumatic sprayer.Positively charged microdroplets from the sprayer (left) are attractedto the negatively charged silver wire electrostatic precipitator wherethey are deposited.

FIG. 4 shows data for a Claisen Schmidt condensation reaction showingratio of product (red) to reactant (yellow) for (top) 5 min bulkreaction, (middle) collection with a 8 kV potential difference betweensprayer (+4 kV) and electrostatic collector, and (bottom) 0 V potentialdifference.

FIG. 5 is a schematic showing another embodiment of the invention inwhich the collector includes an electrostatic precipitator and degassingunit in addition to the condenser.

FIG. 6 is an illustration showing an exemplary data analysis module forimplementing the systems and methods of the invention in certainembodiments.

FIG. 7 is a diagram showing the principle components of a vaporcompressor system.

Temperatures and states of refrigerant at various points in the systemare indicated.

FIG. 8 is a diagram showing a vapor compression system with additions tocomplete the system. Such additions are indicated with arrows.

FIG. 9 shows a mass spectrum of the rinse solution used to recoverproduct from the refrigerator system. The starting material and productpeaks are labeled with their corresponding structures. Note that 1 losesammonia in the source and appears as m/z 134.

DETAILED DESCRIPTION

The invention generally relates to systems and methods for increasingreaction yield. In certain embodiments, the invention provides systems,such as those shown in FIG. 1, for increasing a yield of a chemicalreaction. Such systems may include a pneumatic sprayer configured togenerate a liquid spray discharge from a solvent. The solvent includes aplurality of molecules, a portion of which react with each other withinthe liquid spray discharge to form a reaction product. The system alsoincludes a collector positioned to receive the liquid spray dischargeincluding the unreacted molecules and the reaction product. The systemalso includes a recirculation loop connected from the collector to thepneumatic sprayer in order to allow the unreacted molecules and thereaction product to be recycled through the pneumatic sprayer, therebyallowing a plurality of the unreacted molecules to react with each otheras the unreacted molecules cycle again through the system.

Without being limited by an particular theory or mechanism of action, itis believed that repeatedly spraying, collecting the sprayed material,and re-spraying should build up product even if product formation isincomplete in a single spray event. Collection of the droplets andevaporated solvent is economical and avoids undesirable solvent waste.In certain embodiments, a combination of condensation of vapor andelectrical precipitation of droplets is a means of collection of neutralvapor and charged particulates. The latter, with their cargo of product,can also be collected separately in an electrostatic precipitator.

In general, the systems of the invention can include a spray system inwhich pneumatics and optionally electrical potential are used to createa fine spray, for example an electrosonic spray ionization source, suchas described for example in Takats et al. (Anal. Chem., 2004, 76 (14),pp 4050-4058), the content of which is incorporated by reference hereinin its entirety. The skilled artisan will recognize that any source thatgenerates a liquid spray discharge including small droplets (e.g.,microdroplets), charged or uncharged, can be used with systems andmethods of the invention.

Additional exemplary ionization sources include techniques that utilizeionization sources at atmospheric pressure for mass spectrometry includeelectrospray ionization (ESI; Fenn et al., Science, 246:64-71, 1989; andYamashita et al., J. Phys. Chem., 88:4451-4459, 1984); atmosphericpressure ionization (APCI; Carroll et al., Anal. Chem. 47:2369-2373,1975); and atmospheric pressure matrix assisted laser desorptionionization (AP-MALDI; Laiko et al. Anal. Chem., 72:652-657, 2000; andTanaka et al. Rapid Commun. Mass Spectrom., 2:151-153, 1988). Thecontent of each of these references in incorporated by reference hereinits entirety.

Other exemplary mass spectrometry techniques that work with systems andmethods of the invention utilize direct ambient ionization/samplingmethods that include direct analysis in real time (DART; Cody et al.,Anal. Chem., 77:2297-2302, 2005); Atmospheric Pressure DielectricBarrier Discharge Ionization (DBDI; Kogelschatz, Plasma Chemistry andPlasma Processing, 23:1-46, 2003, and PCT international publicationnumber WO 2009/102766), and electrospray-assisted laserdesorption/ionization (ELDI; Shiea et al., J. Rapid Communications inMass Spectrometry, 19:3701-3704, 2005). The content of each of thesereferences in incorporated by reference herein its entirety.

In certain embodiments, ions of a sample are generated using nanosprayESI. Exemplary nano spray tips and methods of preparing such tips aredescribed for example in Wilm et al. (Anal. Chem. 2004, 76, 1165-1174),the content of which is incorporated by reference herein in itsentirety. NanoESI is described for example in Karas et al. (Fresenius JAnal Chem. 2000 March-April;366(6-7):669-76), the content of which isincorporated by reference herein in its entirety.

The system may also include a collector that includes one or more of thefollowing components. A condenser, such as a cryogenic condenser, may beused in the collector in order to collect vapor phase products. Incertain embodiments, that is all that is required for collection ofreaction product within the liquid spray discharge. In otherembodiments, the collector also includes a liquid degassing unit. Anexemplary liquid degassing unit is a semi-permeable membrane (e.g.silicone polymer) within a vacuum chamber. For example, dimethylsiloxanetubing allows pervaporation of the pneumatic gas into the rough pumpvacuum. Such a unit allows the gas used as the source of pneumatic powerto create the sprayed droplets to escape the closed system. Thecollector may also include an electrostatic precipitator withappropriate applied potentials to collect small charged droplets andthen either wash them back into the main spray reservoir or collect thisproduct-rich material into a separate container. An exemplaryelectrostatic precipitator is commercially available from Clarcor.Another exemplary electrostatic precipitator utilizes negatively chargedsilver wires, as illustrated in FIG. 3.

The system then includes a recirculation line that connects thecollector and the pneumatic sprayer. In that manner, the unreactedmolecules and the reaction product are recycled through the pneumaticsprayer, thereby allowing a plurality of the unreacted molecules toreact with each other as the unreacted molecules cycle again through thesystem.

The Venturi effect, as described in Santos et al. (Analytical Chemistry2011, 83 (4), 1375-1380), can be used to drive flow through therecirculation loop by making the recirculation loop using a Venturitube. Alternatively, the recirculation loop can be operably associatedwith a pump that drives flow from the collector back to the pneumaticsprayer. Since systems of the invention may be closed-loop system, incertain embodiments, the components of the pneumatic sprayer drive flowthrough the entire system.

FIG. 1 illustrates an embodiment of the invention. This embodimentincludes simply a pneumatic sprayer, a cryogenic condenser, and arecirculation loop. In this embodiment, the pneumatic sprayer includes ahigh voltage source so that the produced liquid spray discharge is acharged liquid spray discharge. The high voltage source is an optionalcomponent of the pneumatic sprayer and in certain embodiments, a liquidspray discharge is produced without the need for a high voltage source.In this embodiment though, pneumatics and electrical potential are usedto create a fine spray from a capillary, typically ID 100 microns.

The solvent introduced to the system includes molecules for a reaction,e.g., reactants. Any reactants can be used with systems and methods ofthe invention, e.g., organic or inorganic reactants. The solvent merelyneeds to be compatible with the reactants and the system. The solventflows through the pneumatic sprayer and a liquid spray dischargeincluding the reactants is produced. A portion of the reactants reactwith each other in the liquid spray discharge to produce a reactionproduct.

The pneumatic sprayer may be directly interfaced with the collector,such that the liquid spray discharge is produced directly within thecollector. Alternatively, a tube can be interfaced between the liquidspray discharge and the collector. FIG. 1 shows that a tube isinterfaced between the liquid spray discharge and the collector. In thatmanner, the liquid spray discharge travels a farther distance beforereaching the collector. The greater distance allows for a longer timeperiod for the reaction to occur. By controlling the distance betweenthe pneumatic sprayer and the collector, e.g., by using tubes of varyingdistance, the extent of the formation of reaction product can becontrolled. The longer the tube, the greater the distance the liquidspray discharge travels before reaching the condenser, the longer thetime period the reactants have to react with each other in the liquidspray discharge. Control of droplet size and heating can also be used tocontrol the extent of the formation of the reaction product. A heatercan be included in the elongate member of the pneumatic sprayer or both.

The collector is positioned to receive the liquid spray discharge asshown in FIG. 1. The collector in FIG. 1 includes only a condenser,illustrated here as a cryogenic condenser. As discussed below, thecollector can include more than just a condenser. Any commerciallyavailable cryogenic condenser can be used with systems of the invention,such as those sold by Air Products and Chemicals, Inc.

The liquid spray discharge includes reaction product and unreactedmolecules. When the liquid spray discharge is introduced to thecondenser, the liquid spray discharge is condensed back to solvent,which includes the reaction product and any unreacted molecules. Theinvention recognizes that to increase a yield of the reaction, thesolvent including the reaction product and any unreacted molecules isrecirculated by through the system. In that manner, unreacted moleculesare given a chance to react and incomplete reactions can be driven tocompletion, thereby increasing the yield of the chemical reaction. Toaccomplish that, the systems of the invention include a recirculationloop as shown in FIG. 1. The recirculation loop connects the condenserback to the pneumatic sprayer to allow the solvent including thereaction product and any unreacted molecules to be re-sprayed by thepneumatic sprayer. The embodiment shown in FIG. 1 uses the Venturieffect to drive flow through the recirculation loop. As alreadydiscussed above, the skilled artisan will recognize that othermechanisms can be used to drive flow through the system.

In certain embodiments, an electrostatic precipitator is used in thecollector instead of or in addition to the condenser. Numerous differenttypes of electrostatic precipitators can be used with the systems andmethods of the invention. FIG. 2 shows an exemplary process by whichelectrostatic precipitation occurs. FIG. 3 provides an example of anelectrostatic precipitator. FIG. 3 shows a photograph of a simplecharged droplet spray system connected to a simple silver wireelectrostatic precipitator system. The spray potential and the potentialon the electrostatic precipitator are both independently variable. Thisallowed variation in the potential difference from 0 to 8 kV. It alsoallowed operation in the reverse mode (positively charged droplets andnegatively charged collector). In this embodiment, positively chargedmicrodroplets from the sprayer (left) are attracted to the negativelycharged silver wire electrostatic precipitator where they are deposited.

FIG. 5 shows another embodiment of the invention in which the collectorincludes the condenser, the electrostatic precipitator, and the liquiddegassing unit. The system configuration is shown in FIG. 5. Again, thehigh voltage source is optional.

In certain embodiments, the systems of the invention include a bench-topor miniature mass spectrometer, such as described for example in Gao etal. (Z. Anal. 15 Chem. 2006, 78, 5994-6002), Gao et al. (Anal. Chem.,80:7198-7205, 2008), Hou et al. (Anal. Chem., 83:1857-1861, 2011), Sokolet al. (Int. J. Mass Spectrom., 2011, 306, 187-195), Xu et al. (JALA,2010, 15, 433-439); Ouyang et al. (Anal. Chem., 2009, 81, 2421-2425);Ouyang et al. (Ann. Rev. Anal. Chem., 2009, 2, 187-25 214); Sanders etal. (Euro. J. Mass Spectrom., 2009, 16, 11-20); Gao et al. (Anal. Chem.,2006, 78(17), 5994-6002); Mulligan et al. (Chem. Com., 2006, 1709-1711);and Fico et al. (Anal. Chem., 2007, 79, 8076-8082), the content of eachof which is incorporated herein by reference in its entirety.

An exemplary miniature mass spectrometer is described, for example inGao et al. (Anal. Chem. 2008, 80, 7198-7205.), the content of which isincorporated by reference herein in its entirety. In comparison with thepumping system used for lab-scale instruments with thousands of watts ofpower, miniature mass spectrometers generally have smaller pumpingsystems, such as a 18 W pumping system with only a 5 L/min (0.3 m3/hr)diaphragm pump and a 11 L/s turbo pump for the system described in Gaoet al. Other exemplary miniature mass spectrometers are described forexample in Gao et al. (Anal. Chem., 2008, 80, 7198-7205.), Hou et al.(Anal. Chem., 2011, 83, 1857-1861.), PCT/US17/26269 to Purdue ResearchFoundation, and Sokol et al. (Int. J. Mass Spectrom., 2011, 306,187-195), the content of each of which is incorporated herein byreference in its entirety.

The mass spectrometer may be interfaced online with the system or usedoff-line. In on-line embodiments, a tube can be connected to theelectrostatic precipitator, the condenser, or the recirculation line. Aportion of the solvent is diverted from the system and to the massspectrometer. In such embodiment, the flow can go directly into anotherpneumatic sprayer, including a paper spray probe as described forexample in U.S. Pat. No. 8,859,956, the content of which is incorporatedby reference herein in its entirety, in order to generate a dischargethat can be sent into the mass spectrometer.

In off-line embodiments, a portion of solvent is obtained from theelectrostatic precipitator, the condenser, or the recirculation line andthen analyzed by mass spectrometry.

Experiments were done with a variety of voltage settings, with variousspray distances and pneumatic pressures and flow rates to vary dropletsize and flux. The main results of these experiments are shown in FIG.4, which compares product formation in bulk phase (5 min reaction time)with a 5 min spray time at −4 kV/+4 kV and shows an increase of a factorof 5 in product formation and collection. The zero potential case showedno increase in product formation over bulk. In fact droplet collectionwas very poor and the total amount collected was an order of magnitudeless than with the high potential difference. The same level ofacceleration is noted when the polarity is flipped, i.e. +4 kV/-4 kVresults in an acceleration factor of 5 with similar product collection.

System Architecture

In certain embodiments, the systems and methods of the invention can becarried out using automated systems and computing devices. Specifically,aspects of the invention described herein can be performed using anytype of computing device, such as a computer, that includes a processor,e.g., a central processing unit, or any combination of computing deviceswhere each device performs at least part of the process or method. Insome embodiments, systems and methods described herein may be controlledusing a handheld device, e.g., a smart tablet, or a smart phone, or aspecialty device produced for the system.

Systems and methods of the invention can be performed using software,hardware, firmware, hardwiring, or combinations of any of these.Features implementing functions can also be physically located atvarious positions, including being distributed such that portions offunctions are implemented at different physical locations (e.g., imagingapparatus in one room and host workstation in another, or in separatebuildings, for example, with wireless or wired connections).

Processors suitable for the execution of computer program include, byway of example, both general and special purpose microprocessors, andany one or more processor of any kind of digital computer. Generally, aprocessor will receive instructions and data from a read-only memory ora random access memory or both. The essential elements of computer are aprocessor for executing instructions and one or more memory devices forstoring instructions and data. Generally, a computer will also include,or be operatively coupled to receive data from or transfer data to, orboth, one or more mass storage devices for storing data, e.g., magnetic,magneto-optical disks, or optical disks. Information carriers suitablefor embodying computer program instructions and data include all formsof non-volatile memory, including by way of example semiconductor memorydevices, (e.g., EPROM, EEPROM, solid state drive (SSD), and flash memorydevices); magnetic disks, (e.g., internal hard disks or removabledisks); magneto-optical disks; and optical disks (e.g., CD and DVDdisks). The processor and the memory can be supplemented by, orincorporated in, special purpose logic circuitry.

To provide for interaction with a user, the subject matter describedherein can be implemented on a computer having an I/O device, e.g., aCRT, LCD, LED, or projection device for displaying information to theuser and an input or output device such as a keyboard and a pointingdevice, (e.g., a mouse or a trackball), by which the user can provideinput to the computer. Other kinds of devices can be used to provide forinteraction with a user as well. For example, feedback provided to theuser can be any form of sensory feedback, (e.g., visual feedback,auditory feedback, or tactile feedback), and input from the user can bereceived in any form, including acoustic, speech, or tactile input.

The subject matter described herein can be implemented in a computingsystem that includes a back-end component (e.g., a data server), amiddleware component (e.g., an application server), or a front-endcomponent (e.g., a client computer having a graphical user interface ora web browser through which a user can interact with an implementationof the subject matter described herein), or any combination of suchback-end, middleware, and front-end components. The components of thesystem can be interconnected through network by any form or medium ofdigital data communication, e.g., a communication network. For example,the reference set of data may be stored at a remote location and thecomputer communicates across a network to access the reference set tocompare data derived from the female subject to the reference set. Inother embodiments, however, the reference set is stored locally withinthe computer and the computer accesses the reference set within the CPUto compare subject data to the reference set. Examples of communicationnetworks include cell network (e.g., 3G or 4G), a local area network(LAN), and a wide area network (WAN), e.g., the Internet.

The subject matter described herein can be implemented as one or morecomputer program products, such as one or more computer programstangibly embodied in an information carrier (e.g., in a non-transitorycomputer-readable medium) for execution by, or to control the operationof, data processing apparatus (e.g., a programmable processor, acomputer, or multiple computers). A computer program (also known as aprogram, software, software application, app, macro, or code) can bewritten in any form of programming language, including compiled orinterpreted languages (e.g., C, C++, Perl), and it can be deployed inany form, including as a stand-alone program or as a module, component,subroutine, or other unit suitable for use in a computing environment.Systems and methods of the invention can include instructions written inany suitable programming language known in the art, including, withoutlimitation, C, C++, Perl, Java, ActiveX, HTMLS, Visual Basic, orJavaScript.

A computer program does not necessarily correspond to a file. A programcan be stored in a file or a portion of file that holds other programsor data, in a single file dedicated to the program in question, or inmultiple coordinated files (e.g., files that store one or more modules,sub-programs, or portions of code). A computer program can be deployedto be executed on one computer or on multiple computers at one site ordistributed across multiple sites and interconnected by a communicationnetwork.

A file can be a digital file, for example, stored on a hard drive, SSD,CD, or other tangible, non-transitory medium. A file can be sent fromone device to another over a network (e.g., as packets being sent from aserver to a client, for example, through a Network Interface Card,modem, wireless card, or similar).

Writing a file according to the invention involves transforming atangible, non-transitory computer-readable medium, for example, byadding, removing, or rearranging particles (e.g., with a net charge ordipole moment into patterns of magnetization by read/write heads), thepatterns then representing new collocations of information aboutobjective physical phenomena desired by, and useful to, the user. Insome embodiments, writing involves a physical transformation of materialin tangible, non-transitory computer readable media (e.g., with certainoptical properties so that optical read/write devices can then read thenew and useful collocation of information, e.g., burning a CD-ROM). Insome embodiments, writing a file includes transforming a physical flashmemory apparatus such as NAND flash memory device and storinginformation by transforming physical elements in an array of memorycells made from floating-gate transistors. Methods of writing a file arewell-known in the art and, for example, can be invoked manually orautomatically by a program or by a save command from software or a writecommand from a programming language.

Suitable computing devices typically include mass memory, at least onegraphical user interface, at least one display device, and typicallyinclude communication between devices. The mass memory illustrates atype of computer-readable media, namely computer storage media. Computerstorage media may include volatile, nonvolatile, removable, andnon-removable media implemented in any method or technology for storageof information, such as computer readable instructions, data structures,program modules, or other data. Examples of computer storage mediainclude RAM, ROM, EEPROM, flash memory, or other memory technology,CD-ROM, digital versatile disks (DVD) or other optical storage, magneticcassettes, magnetic tape, magnetic disk storage or other magneticstorage devices, Radiofrequency Identification tags or chips, or anyother medium which can be used to store the desired information andwhich can be accessed by a computing device.

As one skilled in the art would recognize as necessary or best-suitedfor performance of the methods of the invention, a computer system ormachines of the invention include one or more processors (e.g., acentral processing unit (CPU) a graphics processing unit (GPU) or both),a main memory and a static memory, which communicate with each other viaa bus.

In an exemplary embodiment shown in FIG. 6, system 200 can include acomputer 249 (e.g., laptop, desktop, or tablet). The computer 249 may beconfigured to communicate across a network 209. Computer 249 includesone or more processor 259 and memory 263 as well as an input/outputmechanism 254. Where methods of the invention employ a client/serverarchitecture, an steps of methods of the invention may be performedusing server 213, which includes one or more of processor 221 and memory229, capable of obtaining data, instructions, etc., or providing resultsvia interface module 225 or providing results as a file 217. Server 213may be engaged over network 209 through computer 249 or terminal 267, orserver 213 may be directly connected to terminal 267, including one ormore processor 275 and memory 279, as well as input/output mechanism271.

System 200 or machines according to the invention may further include,for any of I/O 249, 237, or 271 a video display unit (e.g., a liquidcrystal display (LCD) or a cathode ray tube (CRT)). Computer systems ormachines according to the invention can also include an alphanumericinput device (e.g., a keyboard), a cursor control device (e.g., amouse), a disk drive unit, a signal generation device (e.g., a speaker),a touchscreen, an accelerometer, a microphone, a cellular radiofrequency antenna, and a network interface device, which can be, forexample, a network interface card (NIC), Wi-Fi card, or cellular modem.

Memory 263, 279, or 229 according to the invention can include amachine-readable medium on which is stored one or more sets ofinstructions (e.g., software) embodying any one or more of themethodologies or functions described herein. The software may alsoreside, completely or at least partially, within the main memory and/orwithin the processor during execution thereof by the computer system,the main memory and the processor also constituting machine-readablemedia. The software may further be transmitted or received over anetwork via the network interface device.

INCORPORATION BY REFERENCE

References and citations to other documents, such as patents, patentapplications, patent publications, journals, books, papers, webcontents, have been made throughout this disclosure. All such documentsare hereby incorporated herein by reference in their entirety for allpurposes.

EQUIVALENTS

Various modifications of the invention and many further embodimentsthereof, in addition to those shown and described herein, will becomeapparent to those skilled in the art from the full contents of thisdocument, including references to the scientific and patent literaturecited herein. The subject matter herein contains important information,exemplification and guidance that can be adapted to the practice of thisinvention in its various embodiments and equivalents thereof.

EXAMPLES

A system that carries out organic reactions at an accelerated rate on amacroscopic scale is described. The design is based upon a vaporcompression system that continuously cycles a solvent from a liquid to avapor. During the transition from liquid to vapor, droplets are created.Reagents added to the system react within these droplets at anaccelerated rate. The system operates at a scale that could produces mgquantities of product with no loss of solvent.

Example 1: System for Increasing a Yield of a Chemical Reaction

The ability to rapidly synthesize mg-kg quantities of organic moleculesof interest to the pharmaceutical industry, chemical manufacturers, andorganic chemists in general; however, this is often not possible becausemany organic reactions take a significant amount of time (sometimesdays) to complete. Methods that accelerate the rates of organicreactions would enable the synthesis of a wide variety of targets in atime-efficient manner.

It has been demonstrated that organic reactions were accelerated whenthey occurred in the charged microdroplets generated by desorptionelectrospray ionization (DESI). Since that time, there have been severalreports that describe many different reactions that are accelerated inmicrodroplets (or other confined volume regions such as thin films),most of which involve charged microdroplets generated by electro sprayionization (ESI).

There are several theories as to why reactions are accelerated incharged microdroplets. Through repeated cycles of evaporation andcolumbic fission, the droplets generated in ESI shrink over time. Thisconcentrates the reagents within the droplets increasing the frequencywith which they undergo collisions. If the reagents are charged orhydrophobic (assuming a polar solvent such as water, methanol, oracetonitrile is used), they are more likely to reside on the surface ofthe droplet. This provides a further concentration effect as thereagents are restricted to the surface rather than traveling thedroplet. It also reduces the solvation of the reagents because they arelocated at the solvent-air inter-face. This reduction in solvationlowers the activation energy barrier of the reaction further increasingthe rate. Another factor which may contribute to the rate enhancement ofacid or base catalyzed reactions is that the pH within the dropletslikely reaches extremes because charge (either positive or negativedepending on the polarity of the applied voltage) concentrates in thedroplets as they shrink.

Microdroplets are not the only method by which reactions have beenaccelerated, and other possible approaches include sonication orirradiation with microwaves to increase the rates of organic reactions.When compared to the techniques that use microdroplets, these methodsappear to be harsher because they rely on generating regions within thereaction mixture that have extremely high temperatures or pressures;however, they do have the advantage of being larger scale techniquesthat are able to produce macroscopic quantities of product.

There have been efforts to use the reaction acceleration provided bymicrodroplets to produce mg quantities of products; however, thesetechniques rely on the continuous evaporation of solvent. Depending onthe solvent used, this constant consumption of solvent results in thesetechniques being environmentally unfriendly, expensive, and/or unsafefor user.

To harness the power of the reaction rate enhancements provided bymicrodroplets while eliminating the issue of solvent consumption, wehave designed a process in which organic reactions are carried outwithin a vapor compression system (VCS).

A VCS (FIG. 7) is the means by which refrigerators and air conditionersprovide cooling. There are four main parts of a VCS: the compressor,condenser, evaporator, and expansion device. The entire system is sealedin a gas-tight manner and has a fixed volume. These systems aretypically evacuated using a vacuum pump to remove contaminants, and thena certain quantity of a low boiling point liquid called a refrigerant isadded to the system. An example of a commonly used refrigerant is R-134a(1,1,1,2-tetrafluoroethane).

A VCS provides cooling by repeatedly cycling the refrigerant between theliquid and vapor phases. Inside of the evaporator, the refrigerantevaporates from a liquid to a vapor. During this process, it absorbsheat from the surrounding air. Inside of the condenser, the refrigerantcondenses back a liquid. This process releases the heat that wasabsorbed by the refrigerant in the evaporator to the surroundingenvironment. If the evaporator is placed inside a refrigerator (or ahome in the case of air conditioning) while the condenser is placed onthe outside, the system will “pump” heat from the inside to the outsidelowering the temperature within the unit.

The control over the evaporating and condensing temperatures of therefrigerant is provided by the combination of the compressor and theexpansion device. The compressor is a pump which pulls vapor from theevaporator side of the system and pushes it into the condenser side ofthe system. The expansion device simply provides a flow restrictionbetween the two sides of the system. This means that when the compressoris turned on, a greater quantity of vapor is added to the condenser sideduring each cycle of the compressor than can flow out through theexpansion device. Correspondingly, more vapor is removed from theevaporator during each compressor cycle than flows in through theexpansion device. This increases the pressure within the condenser andlowers the pressure within the evaporator. This is why the condenser andevaporator regions of the system are often called the high and low sidesrespectively.

The result of the high pressure created within the condenser is that theboiling point of the refrigerant is raised to the point where itcondenses. Refrigerants are typically gases at standard temperature andpressure, so the high pressure created within the condenser is necessaryto force the refrigerant to condense at ambient temperature. Once therefrigerant has reached the end of the condenser, it has fully condensedinto a liquid. This liquid then flows through the expansion device intothe evaporator. The low pressure within the evaporator lowers theboiling point of the refrigerant causing it to evaporate. Once therefrigerant reaches the end of the evaporator it has completelyevaporated into a gas. This gas then flows into the compressor, and thecycle repeats. We propose that a VCS could be used to carry out organicreactions in an accelerated manner while conserving solvent. This ispossible because a spray is created at the exit of the expansion devicebecause some of the liquid refrigerant flash vaporizes into a gas whenit is exposed to the low pressure of the evaporator. The droplets thatare generated in this spray could serve as accelerated reactors ifreagents are added to the system with the refrigerant. Since therefrigerant that evaporates from these droplets is contained within thesystem, no solvent is lost during this process. There is also thepossibility that thin film effects could lead to reaction accelerationwhen the liquid refrigerant splashes against and coats the walls of theevaporator during the non-linear path it takes back to the compressor.

This Example illustrates a VCS system that can be used as an acceleratedorganic reactor. Because these systems are typically sealed from theoutside environment, a ways to add reagents and remove product wasengineered. A way to allow for features such as online monitoring ofreaction progress was also engineered.

A Fisher Scientific model 97-960-1 miniature refrigerator was used asthe basis of a design. This model is a sealed unit (no access ports)which uses R-134a as the refrigerant and has a capillary tube as theexpansion device. A capillary tube is a long section of very narrowdiameter tubing that creates a flow restriction between the condenserand evaporator. The stock condenser and evaporator coils were made outof steel and aluminum respectively. These metals are more challenging tomanipulate than copper, so they were removed, and new condenser andevaporator coils were made from ¼ in. ACR copper tubing. These new coilswere designed to be approximately equal in volume to the original coilsso that they would be compatible with the stock compressor.

The design of the system is laid out in FIG. 8. Joints between coppertubes in refrigeration systems are typically brazed because brazedjoints are strong and leak-free; however, brazed joints do not allow forrepeated removal and attachment of the joint. Because our systemrequires repeated opening to add reagents and remove product, the jointsin our system were made using ¼ in. flare fittings. These fittings aregas-tight and can be repeatedly removed and attached.

Reagents will be added by undoing the flare fitting located on theliquid line, which is the tubing that connects the condenser to theexpansion device. Since under normal operating conditions warm liquidrefrigerant flows in the liquid line, the reagents should dissolvequickly.

A small chamber with a window, called a sight glass, was added to theliquid line after the above mentioned flare fitting. This allows forvisual observation of the flow of liquid refrigerant through the systemand will help detect problems such as reagents not dissolving.

Service ports were added immediately preceding and following thecompressor. These ports allow for the attachment of a manifold gaugeset. A manifold gauge set is used to monitor the pressures of the highand low sides of the system as well as pull a vacuum and add or removerefrigerant. A manifold gauge set consists of three hoses and twogauges. One hose connects to the low side service port, and one gaugereads the pressure on this hose. Another hose connects to the high sideservice port, and the second gauge reads the pressure on this hose. Thethird hose (called the utility hose) can connect to a vacuum pump,refrigerant cylinder, or recovery machine depending on the service beingperformed.

The capillary tube that was originally used as the expansion device wasremoved, and a needle valve was installed in its place. A needle valveallows for adjustment the of flow restriction between the condenser andevaporator which allows for some control over the pressures in the highand low sides. Adjusting the pressures in the evaporator and condenserchanges the evaporating and condensing temperatures of the refrigerant.This is important because under normal operation of the system, theevaporating temperature of R-134a was approximately −10° C. It isunclear how reaction acceleration in microdroplets would be affected bysuch a low temperature, and it would be desirable to have control overthe evaporating temperature so that its effects can be studied.

The reactions that have been targeted for the initial tests of thesystem are alkylation reactions involving various benzylamines andbenzyl bromides. These reactions were chosen because they have beensuccessfully used in previous reaction acceleration studies, and they donot require the addition of an acid or base, which could potentiallydamage the system. They do produce HBr as a byproduct, but they systemwill likely be run for only a short period of time, so the impact ofthis byproduct should be minimal.

The appropriate quantities of reagents will weighed onto weighing paper.The weighing paper will be rolled into a cylinder and used to dispensethe reagents directly into the liquid line at the joint following thecondenser. The joint will be reconnected, and a manifold gauge set willbe attached to the high and low side service ports. The utility hose ofthe manifold gauge set will be attached to a vacuum pump, and a vacuumwill be pulled on the system.

The utility hose will then be attached to a canister of R-134arefrigerant, and approximately 85 grams of R-134a will be charged intothe system. 85 grams was the amount of refrigerant originally chargedinto the Fisher Scientific miniature refrigerator, so it will be used atthe starting point; however, the charge can be adjusted to optimize thesystem's performance. The system will be turned on and allowed to runfor some amount of time. The system will then be turned off, and theutility hose of the manifold gauge set will be attached to a refrigerantrecovery machine. A recovery machine is used to pull refrigerant out ofa system, condense it into a liquid, and then store it in a refrigerantrecovery cylinder. A recovery machine can remove refrigerant as either aliquid or a gas. In these experiments, the refrigerant will be removedas a gas so that any product remains in the system.

Once the refrigerant has been evacuated, the condenser and evaporatorwill be removed from the system. They will both be flushed with solventto recover any product, leftover starting material, and/or byproductsthat are present.

The system will be run for different lengths of time to determine howquickly product forms within the system. It will also be run with theneedle valve in various positions to observe the impact of changing theevaporating temperature on reaction acceleration.

A complicating factor in this experiment is the presence of oil in thecompressor. Most refrigeration compressors are designed such that oilflows around all of the components contained within the compressorhousing. This means that oil is present in the cylinder when therefrigerant vapor is compressed and consequently small amounts of oiltravel with the refrigerant throughout the vapor compression system.

The oils used in R-134a systems are polyolester oils. These oils areesters made by combining pentaerythritol with various fatty acids. It isunclear whether or not the small amount of oil circulating throughoutthe system will interfere with the reactions. Another complicatingfactor is that these oils often contain additives to neutralize acid orprevent wear, and these may also interfere with the reactions.

If the oil does end up being a problem, an oil-free compressor could beused and they do not circulate oil. If the additives within the oilpresent a problem, polyolester oil which does not contain additives isavailable.

Assuming the design of the system is successful, there are severalmodifications within the scope of the invention. For example, thecurrent system is designed for use with R-134a as the refrigerant. Thiswas chosen because that was the refrigerant used in the FisherScientific miniature refrigerator. Other solvents may be used instead ofR-134a with additional modifications to the system. For example, itwould be desirable if the solvents commonly used in organiclaboratories, such as methanol, acetonitrile, and dichloromethane,worked in this system. These solvent are all liquids at room temperatureand atmospheric pressure. These solvents could potentially work in thesystem if the evaporator was heated, for example by wrapping it withheating tape, beyond the boiling points of these solvents. Thesesolvents could also be made to evaporate at room temperature (or below)by lowering the pressure in the evaporator to vacuum levels. This ispossible with the current compressor if the needle valve is barelyopened, creating an increased flow restriction between the condenser andevaporator.

The invention also contemplates incorporating online monitoring of thereaction progress, preferentially by mass spectrometry. A needle valvewith a tube extending from it could be incorporated somewhere along theliquid line to achieve this purpose. This needle valve could be crackedallowing a small volume of liquid to escape from the end of the tube. Avoltage could be applied to the tube forming an electro spray plumewhich can be directed towards the inlet of a mass spectrometer. Asimilar valve could be placed somewhere along the evaporator to monitorreaction progress there. This works best if the heating method is usedto induce evaporation because this creates an elevated pressure withinthe evaporator allowing liquid/vapor to flow out. Ultimately a systemsuch as this would be most useful if a means was developed by whichreagents could be added continuously and product could be removedcontinuously. This might be possible if the product cycles back to thecondenser. A port could be added just after the condenser from whichsolvent is continuously drawn and product is collected. Another portcould be added downstream, possibly right before the expansion device,into which reagents are continuously pumped at the same flow rate asproduct is being removed.

Example 2: Reaction of 4-Dimethylaminobenzylamine and Benzyl BromideUsing Systems of the Invention

The following reaction Scheme 1 was carried out using systems of theinvention.

15.4 uL of 1 (4-dimethylaminobenzylamine) and 12.5 uL of 2 (benzylbromide) were pipetted into the condenser coil of a refrigeration systemthat includes a compressor from a miniature refrigerator, evaporator andcondenser coils constructed from copper tubing, and a needle valveacting as the expansion device. 100 mL of R-134a(1,1,1,2-tetrafluoroethane) was then added to the system. The compressorwas turned on, and the system was allowed to run for 65 minutes. Thecondensing temperature during the experiment was 51° C., and theevaporating temperature was 8.6° C. After 65 minutes, the compressor wasturned off, and the R-134a was removed using a refrigerant recoverymachine. The condenser coil, needle valve, and evaporator coil were thenrinsed as a unit with 425 mL of dichloromethane, followed by 1000 mL ofethanol, followed by 300 mL of water. These three solutions were thencombined and analyzed by nESI on a Thermo LTQ to give the mass spectrumshown in FIG. 9.

1-20. (canceled)
 21. A method for increasing yield of a chemicalreaction, the method comprising: generating a liquid spray dischargeusing a pneumatic sprayer, wherein the liquid spray discharge isgenerated from a solvent that comprises a plurality of molecules, aportion of which react with each other within the liquid spray dischargeto form a reaction product; collecting in a collector the liquid spraydischarge comprising unreacted molecules and the reaction product; andrecirculating the unreacted molecules and the reaction product throughthe pneumatic sprayer, in order to allow a plurality of the unreactedmolecules in the solvent to react with each other as the unreactedmolecules cycle again through the pneumatic sprayer, thereby increasinga yield of the chemical reaction.
 22. The method according to claim 21,wherein a voltage source is operably associated with the pneumaticsprayer in order to generate a charged liquid spray discharge.
 23. Themethod according to claim 22, wherein collecting comprises condensingthe liquid spray discharge into a reservoir of the collector.
 24. Themethod according to claim 23, wherein condensing uses a cryogeniccondenser.
 25. The method according to claim 23, wherein collectingfurther comprises precipitating liquid droplets from any liquid spraydischarge not captured in the condensing step.
 26. The method accordingto claim 25, further comprising degassing gas used by the pneumaticsprayer to generate the liquid spray discharge.
 27. The method accordingto claim 25, wherein degassing uses a liquid degassing unit comprising asemi-permeable membrane within a vacuum chamber.
 28. The methodaccording to claim 26, further comprising analyzing the reactionproduct.
 29. The method according to claim 21, wherein the pneumaticsprayer is an electrosonic spray ionization source.
 30. The methodaccording to claim 21, further comprising controlling an extent offormation of the reaction product by varying a distance between thepneumatic sprayer and the collector.